Project Summary The reasons behind the development of myopia and its increasing incidence, particularly among educated people, remain obscure. The finding that animals can be made myopic or hyperopic by spectacle lenses that shift the plane of focus to behind the retina (hyperopic defocus) or in front of it (myopic defocus) demonstrates that refractive development is under homeostatic control. Because the eye can modulate its growth even if the optic nerve is severed, and because defocus that is restricted to one area only affects the eye growth underlying that area, it follows that the retina controls eye growth. However, despite two centuries of study, prophylactic treatments against childhood myopia are limited to atropine drops, contact lenses that reshape the cornea, or stabilizing treatments for the sclera, all of which have potential side effects and limited efficacy. Decades of work in our three labs has linked the development of ametropias to alterations in ocular circadian rhythms. Recently, we showed that the eye?s response to defocus depended on time of day of exposure, further evidence for the influence of circadian rhythms in myopia development. We also found that 6 clock genes in retina and choroid were altered in eyes responding to myopic or hyperopic defocus. In this application we will look for downstream signals of these clock genes using RNA-Seq to determine molecular signaling pathways that might explain what to target in potential myopia therapies. How the visual environment affects the growth of the eye and influences refractive error in humans continues to generate interest, including contemporary studies relating time spent outdoors to the inhibition of myopia in children, and on the deleterious impact of artificial nighttime lighting on human health in general. Increasing evidence indicates that exposure to light in the evening, especially short wavelengths, affects sleep cycles by altering the rhythm in melatonin. We found that a mere 2 hours of blue evening light stimulated ocular growth and altered ocular rhythms. This application will address the influences of time of day, relative spectral composition and the dopamine and melatonin rhythm on the responses to brief blue light. We will study the role of the ipRGCs, and the potential interaction between hyperopic defocus and blue light. These studies will have implications for the use of light-emitting technologies prior to bed. Our finding that six clock gene transcripts, and melanopsin, showed diurnal cycling in choroid suggests diverse circadian functions for this tissue. We aim to study circadian signaling in choroid, with focus on roles of dopamine and melanopsin. We will localize melanopsin, and in an exploratory series of experiments, we will ask if the rhythm in choroidal thickness is endogenous to the choroid, and address the hypothesis that the choroid is photosensitive. We will use chicks, a species with rapid and well-characterized compensatory responses to visual manipulations, and retinal/visual similarities to humans. We expect that this work will generate novel and useful hypotheses that can be extended to the study of refractive errors in children.